The prior art teaches the use of sustained-release systems, with the aim of providing medicaments which can be administered once a day. Orally administered solid dosage forms have gained more grounds in this respect.
DE Patent Application No. 39 43 242 (FR No. 2 670 112) discloses “matrix” type granules comprising active pharmaceutical ingredients (API) and inert excipent(s) compressible into tablets. Each granule consists of a multitude of said particles included in a roughly spherical matrix comprising a cellulosic polymer, a vinylic or acrylic polymer, a plasticizer and a lubricating agent.
There are reports in the literature of several tablets which are film-coated with a coating material of, for example, cellulosic, acrylic, starch, polyethylene glycol or gum type, or their derivatives. This coating functions to provide taste masking, protection of API, gastro-resistance to physiological fluids, and also to prolong the release of active pharmaceutical ingredients.
For example, U.S. Pat. No. 4,461,759 describes a coated tablet which protects the API from the harmful effects of the acid pH of the stomach and at the same time releasing the API at a constant rate in the gastrointestinal tract.
The use of microporous film coating which allows the release of the API under the effect of an osmotic pressure has also been widely reported. One such report teaches the sustained release of API irrespective of the solubility of the API in the medium. This embodiment is described in patent application WO 91/16885 and in U.S. Pat. No. 5,028,434.
Another practice in the delivery of drugs that abounds in the prior art is the use of micro-particulate pharmaceutical systems giving a sustained release of API.
For example, Patent EP 396,425 discloses a system intended for the administration once daily dose of API. To this end, the API is bound to the surface of inert spherules with a diameter ranging from 250 to 2000 microns, using a known binder. The particles are then film-coated with a cellulose compound and a plasticizer, to slow down the release of the API.
U.S. Pat. No. 5,286,497 describes a formulation based on Diltiazem (AP) which is designed to be taken once a day. The API is bound to the surface of inert granules of sugar or of starch, which are then optionally film-coated.
U.S. Pat. No. 4,869,908 describes floating tablets, characterized by a long residence time in the stomach. This system is more particularly suited to the administration of API having a preferential absorption at the gastric level.
Patent FR 2,395,026 teaches a process for the preparation of a system in which the micro-particles containing the API are in a sustained-release form containing, in their composition, a densifying agent which allows a significant prolongation in the transit time, which may then exceed 24 hours. This system was developed after observation of the fact that transit in the small intestine is slowed down considerably when the density of the particles exceeds 1.4 grams per cubic centimeter. The same approach of increasing the transit time by elevation of the density is adopted in EP applications 0,080,341 and 0,173,210. However, such systems have the drawback of requiring the introduction of a large amount of densifying agent, of the order of 30 to 80% of the total weight of the form, which limits the content of API in the system and constitutes a handicap for the manufacture of forms requiring a large dose of API.
Another approach for controlled release consists of the development of bioadhesive systems.
EP 0,452,268 claims a bucco-adhesive system in the form of microparticles film-coated with a gel of xanthan/carob gums or with ethylcellulose. The effectiveness of such a system, essentially intended for the mouth, is not established, and all the less so since the particles are coated with a film of wax as an outer layer, which is intended to sustain their release but which makes adhesion improbable, and anyway not demonstrated in vivo.
Application EP 0,516,141 is directed towards the development of a bioadhesive particulate system by overcoating, of any given sustained-release form of an AP, with an adhesive composition based on polymers such as water-soluble derivatives of cellulose, acrylic polymers known under the trade names Carbopol® or Polycarbophil®, alginates, gelatin or pectin.
The above described prior art are clearly distinct from the features disclosed in the current invention, more especially by their composition and manufacturing process.
A review of the prior art reveals a large number of unsuccessful attempts directed towards providing a general solution to the controlled release of API for periods which may be up to 24 hours in the case of oral administrations.
Furthermore, none of the prior art takes account of the set of constraints inherent in the production of a multifunctional system which may be applied to the majority of APIs, and no satisfactory solution is available to date.
Indeed, there are a large number of constraints opposing the production of such a system, and there are many difficulties to be solved.
U.S. Pat. No. 6,022,562 discloses an invention which relates to microcapsules for the oral administration of medicinal and/or nutritional API, which are smaller than or equal to 1000 microns in size. These microcapsules consist of particles which are coated with a coating material consisting of a mixture of a film-forming polymer derivative, a hydrophobic plasticizer, a functional agent and a nitrogen-containing polymer. The invention also relates to a process for the production of the said microcapsules.
The claims in U.S. Pat. No. 6,022,562 and the other patents cited from the prior art are significantly different from our disclosure. U.S. Pat. No. 6,022,562 uses multiple film forming polymers in one film forming coating composition, i.e., the polymers are applied as an admixture to form one or more layers of coat. Unlike in our invention there is no attempt to separate each film forming polymer from the other. To the best of our knowledge, there is no prior art teaching the use of multiple polymers each applied separately as a coat, neither does the prior art teach the use of transition coats to modulate the release of materials.
There have been reports in the literature of the use of hydrophobic thermoplastic polymers such as ethylcellulose for the controlled release of pharmaceutical substances. Ethylcellulose is typically applied as a coat. Drug release is by symmetric flow (channel flow) and diffusion through the ethylcellulose layer. Release is controlled by the layer thickness and the rate of channel flow or diffusion flow force. Such systems are at a disadvantage because they allow drug delivery to be controlled via a singular property i.e., coating thickness formed from use of a single film forming admixture. This presents a high risk approach to the optimization of formulations, because the use of coating thickness as an index for controlling rate of input presents a narrow window to work with and limits the applicability of such systems. This is one reason why matrix systems have superceded the use of hydrophobic thermoplastic polymers such as ethylcellulose coats or coats consisting of a mixture of ethylcellulose polymer and a nitrogen-containing polymer such as polyvinylpyrolidone as means for controlling the release of drugs. As stated earlier to the best of our knowledge there is no report in the prior art where more than one thermoplastic polymer has been used to control the release of drugs in which the polymers are applied as transition coats. The object of the present invention is thus to provide a novel composition and a method of using and preparing same in order to control the rate and extent of delivery of granules, tablets, capsules, spheroids, pellets, microspheres, nanospheres, microcapsules, crystals or particles containing one or more of the following; active pharmaceutical ingredients, biological, chemical, nutraceutical, agricultural or nutritional materials. This consists of the use of coats of two or more polymers in which the respective layers of coat of each polymer transition from one coat to another and are not applied as an admixture.